Targeting DHODH Suppresses Melanoma Progression via Pyrimidine Depletion and Mitochondrial Dysregulation.

Abstract

Dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme in de novo pyrimidine biosynthesis, has emerged as a promising therapeutic target in oncology. However, the antitumor efficacy and underlying mechanisms of DHODH inhibitors in melanoma remain incompletely understood. Here, we characterize a novel DHODH inhibitor, ZP0946, and elucidate its anti-melanoma activity and molecular mechanisms. ZP0946 exhibited potent antiproliferative effects on melanoma cells and induced robust S-phase cell cycle arrest. Mechanistically, ZP0946 depleted intracellular pyrimidine pools, and exogenous uridine supplementation abrogated this antiproliferative effect. Mitochondrial functional assays revealed that ZP0946 impaired ATP production, depolarized mitochondrial membrane potential, increased the levels of reactive oxygen species, and reduced the oxygen consumption rate. Exogenous uridine supplementation reversed this mitochondrial dysfunction. In immunodeficient nude mouse xenograft models, ZP0946 significantly suppressed melanoma xenograft growth without inducing detectable toxicity. Notably, compared with immunodeficient tumor-bearing models, the antitumor efficacy of ZP0946 was superior in immunocompetent syngeneic models, with a tumor growth inhibition rate of 78.2%. This enhanced therapeutic effect was accompanied by reduced frequencies of myeloid-derived suppressor cells. Collectively, our findings reveal that DHODH inhibition by ZP0946 exerts dual anti-melanoma effects through pyrimidine depletion and mitochondrial dysfunction, providing a preclinical rationale for targeting DHODH with ZP0946 in melanoma therapy.

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